Thiel-Behnke Corneal Dystrophy

Key Points at a Glance

Highlights of This Disease

• Thiel-Behnke corneal dystrophy (TBCD) is an autosomal dominant Bowman layer dystrophy caused by the Arg555Gln mutation in the TGFBI gene.
• It is characterized by honeycomb-shaped corneal opacities and recurrent corneal epithelial erosions.
• Anterior segment OCT shows a characteristic sawtooth pattern of Bowman’s membrane.
• Curly collagen fibers on electron microscopy are specific to TBCD.
• PTK (phototherapeutic keratectomy) is the first-line treatment, but recurrence occurs.
• Reis-Bücklers corneal dystrophy (RBCD) has a different gene mutation and is distinguished as a separate disease.

1. What is Thiel-Behnke Corneal Dystrophy?

Thiel-Behnke corneal dystrophy (TBCD), also called honeycomb corneal dystrophy, is one of the epithelial-stromal TGFBI-related corneal dystrophies. It is autosomal dominant, and the Arg555Gln (R555Q) mutation in the TGFBI gene located on chromosome 5q31 is the representative causative mutation ^1,2.

TBCD is progressive and bilateral. It initially affects the Bowman layer in the central cornea and progresses to the peripheral cornea and deep stroma with age. It is an extremely rare disease, and its prevalence is unknown; current literature is limited to case series and case reports ¹.

Classification of TGFBI-Related Corneal Dystrophies

Mutations in the TGFBI gene can cause different clinical presentations depending on the specific amino acid change. The 2015 IC3D revision introduced a new anatomical subcategory called epithelial-stromal TGFBI-related dystrophies, which was maintained in the 2024 IC3D Edition 3 ^1,2.

Dystrophy	Mutation
TBCD	Arg555Gln
RBCD	Arg124Leu
Granular type 1	Arg555Trp
Lattice type 1	Arg124Cys

Q What is the difference between TBCD and Reis-Bücklers corneal dystrophy (RBCD)?

A

TBCD and RBCD are both Bowman layer dystrophies caused by TGFBI gene mutations, and were once confused, but are now distinguished as separate diseases based on light and electron microscopic re-evaluation by Küchle et al. (1995) ³. The representative mutation of TBCD is Arg555Gln, and that of RBCD is Arg124Leu ². Clinically, RBCD follows a more aggressive course, presenting with irregular, well-defined opacities. TBCD is characterized by honeycomb-like opacities and a sawtooth pattern ^3,4. Electron microscopy shows curly collagen fibers in TBCD and rod-shaped bodies in RBCD ³. Genetic testing is useful for definitive diagnosis.

2. Main symptoms and clinical findings

Subjective symptoms

• Pain: Pain associated with recurrent corneal epithelial erosions is observed from childhood. The frequency of recurrent erosions decreases with age.
• Decreased visual acuity: As age advances, corneal opacity increases, leading to visual impairment.

Clinical Findings (Findings Confirmed by Doctor’s Examination)

• Honeycomb-shaped corneal opacity: In the early stage, isolated spot-like opacities are seen in Bowman’s layer, which gradually progress to symmetrical subepithelial honeycomb-shaped opacities. In adults, opacities progress from superficial to deep layers and extend to the peripheral cornea^1,3.
• Sawtooth pattern: Anterior segment OCT shows a sawtooth pattern of moderate reflectivity in Bowman’s layer. This is characteristic of TBCD, in contrast to the well-defined hyperreflective band of RBCD⁴.
• Irregular elevation of the corneal surface: Irregularity of the corneal surface is observed with slit-lamp microscopy.

3. Causes and Risk Factors

Causes

The TGFBI gene encodes TGFβ-induced protein (keratoepithelin), which is involved in cell migration, adhesion, differentiation, and growth. The Arg555Gln mutation is thought to cause keratoepithelin to aggregate into abnormal deposits within the corneal tissue².

The most common mutation in TBCD is Arg555Gln, but other mutations such as Met502Val/Arg555Gln and Gly623_His626del have also been reported².

Inheritance Pattern

Autosomal dominant inheritance. A parent with the mutation has a 50% chance of passing it to each child.

Genetic Counseling

Since TBCD is autosomal dominant, confirming family history is important. Genetic testing of the TGFBI gene is useful for definitive diagnosis. The frequency of recurrent corneal erosion tends to decrease with age, but corneal opacity progresses gradually, so regular ophthalmologic follow-up is necessary.

4. Diagnosis and Examination Methods

Imaging Tests

Slit-lamp microscopy: Confirms honeycomb-shaped subepithelial opacities. In the early stage, they appear as isolated spot-like opacities¹.

Anterior segment OCT: Shows a sawtooth pattern of moderate reflectivity extending toward the epithelial side of Bowman’s layer. It is distinguished from the well-defined high-reflectance band of RBCD by its unclear borders, and is useful for non-invasive in vivo differentiation⁴.

Confocal microscopy: Depicts irregular reflective deposits within Bowman’s layer and the epithelium¹.

Pathology and Genetic Testing

Electron microscopy: Curly collagen fibers are pathognomonic for TBCD. In RBCD, rod-shaped bodies are observed, allowing differentiation³.

Genetic testing: Confirms the Arg555Gln mutation in the TGFBI gene. It is most useful for definitive diagnosis^1,2.

Light microscopy: Bowman’s layer is replaced by fibrocellular pannus, which stains positive with Masson’s trichrome stain³.

Differential Diagnosis

Differentiation from RBCD is most important, and genetic testing is essential because the clinical appearance is similar. Lattice corneal dystrophy type 1 presents with linear opacities due to amyloid deposition, and granular corneal dystrophy type 1 presents with hyaline-like granular opacities. Both are TGFBI gene mutations, but the mutation sites differ.

Q What are curly collagen fibers?

A

Curly collagen fibers are a specific finding observed by electron microscopy in TBCD. They exhibit a morphology different from normal collagen fibers and accumulate in TBCD tissue. In RBCD, rod-shaped bodies are a specific finding, and this difference in electron microscopy findings helps differentiate the two diseases. However, since electron microscopy is not clinically easy, TGFBI genetic testing is recommended for definitive diagnosis.

5. Standard Treatment

There is no consensus on the optimal treatment for TBCD.

Conservative Treatment

For recurrent corneal epithelial erosions, frequent artificial tear instillation, hypertonic saline eye drops, and protection with therapeutic contact lenses are performed.

PTK (Phototherapeutic Keratectomy)

PTK is the first-line treatment for early stages. It removes corneal opacities and improves vision. In a medium-term study of 10 eyes of 5 genetically confirmed TBCD patients by Hieda et al. (2013), mean logMAR BCVA improved by −0.55, and stable visual acuity and corneal transparency were achieved in the medium term. However, recurrence occurs after PTK; in that report, recurrence of superficial central opacities was observed in 5 of 10 eyes, and 4 of those eyes had a visual acuity drop of 2 lines or more ⁵. Since one PTK session removes approximately 50 μm of corneal stroma, the number of sessions is limited ².

Corneal Transplantation

In cases with repeated recurrence after PTK, superficial keratoplasty or deep lamellar keratoplasty is indicated depending on the depth of opacity. Even after corneal transplantation, recurrence may occur in the superficial layer of the graft stroma covered by host corneal epithelium. If recurrence is repeated and deposits reach the deep stroma, penetrating keratoplasty is required ^1,2.

Bowman Layer Transplantation

Recently, Bowman layer onlay transplantation using donor Bowman layer has been reported as a promising surgical intervention. It is less invasive than conventional lamellar keratoplasty and has the advantage of preserving more of the recipient’s corneal tissue while reducing the risk of recurrence and graft complications.

Treatment Considerations

The recurrence rate after PTK and corneal transplantation is high, and multiple procedures may be necessary. In TGFBI dystrophy, because the abnormal protein originates from the corneal epithelium, recurrence can occur at the interface between the epithelium and the graft even when superficial transplantation is chosen. The number of PTK sessions is limited by corneal thickness, so planned management considering future treatment options is important.

6. Pathophysiology and Detailed Mechanisms

Abnormal Deposition of Keratoepithelin

Keratoepithelin, the product of the TGFBI gene, becomes aggregated protein due to gene mutations and deposits in corneal tissue. Since different mutations form different aggregates, even mutations in the same TGFBI gene can result in different clinical presentations. In TBCD, deposits appear as curly collagen fibers, while in RBCD, they appear as rod-shaped bodies ^2,3.

Impaired Autophagy

It has been hypothesized that impaired autophagy leads to accumulation of mutant TGFBI protein in corneal fibroblasts. Normally, unnecessary proteins are degraded by autophagy, but when this mechanism is impaired, abnormal proteins accumulate and corneal opacity progresses ².

Histological Findings

The epithelial cell layer becomes uneven in thickness, with partial defects in the basal epithelial cell layer. Fibrous tissue forms in a sawtooth pattern between the epithelium and stroma. Bowman’s membrane is replaced by fibrocellular pannus, which stains positive with Masson’s trichrome stain ³.

Q How often does recurrence occur after PTK?

A

Recurrence after PTK is inevitable, but the timing differs depending on whether the mutation is homozygous or heterozygous. In a study by Hieda et al. of 10 eyes from 5 patients with genetically confirmed TBCD, mean logMAR BCVA improved by −0.55, while 5 of 10 eyes showed recurrence of superficial central opacity, and 4 of those eyes experienced a decrease in visual acuity of 2 lines or more ⁵. In heterozygotes, the course to recurrence is relatively slow, and few cases require retreatment. In contrast, in homozygotes, recurrence occurs 1–2 years after surgery, and repeated PTK or corneal transplantation is often required ². Recurrence occurs on the epithelial repair surface after PTK, that is, at the interface between the epithelium and stroma.

Medical Information Disclaimer

The content of this article is intended for informational purposes for medical professionals and does not constitute a basis for individual diagnosis or treatment. Clinical decisions according to the patient’s condition should be made by the attending physician.

8. References

1. Weiss JS, Rapuano CJ, Seitz B, et al. IC3D Classification of Corneal Dystrophies—Edition 3. Cornea. 2024;43(4):466-527. PMID: 38359414. PMCID: PMC10906208. doi:10.1097/ICO.0000000000003420. PubMed
2. Lakshminarayanan R, Chaurasia SS, Anandalakshmi V, et al. Clinical and genetic aspects of the TGFBI-associated corneal dystrophies. Ocul Surf. 2014;12(4):234-251. PMID: 25284770. doi:10.1016/j.jtos.2013.12.002. PubMed
3. Küchle M, Green WR, Völcker HE, Barraquer J. Reevaluation of corneal dystrophies of Bowman’s layer and the anterior stroma (Reis-Bücklers and Thiel-Behnke types): a light and electron microscopic study of eight corneas and a review of the literature. Cornea. 1995;14(4):333-354. PMID: 7671605. doi:10.1097/00003226-199507000-00001. PubMed
4. Nishino T, Kobayashi A, Mori N, Yokogawa H, Sugiyama K. In vivo Imaging of Reis-Bücklers and Thiel-Behnke Corneal Dystrophies Using Anterior Segment Optical Coherence Tomography. Clin Ophthalmol. 2020;14:2601-2607. PMID: 32982153. PMCID: PMC7490037. doi:10.2147/OPTH.S265136. PubMed
5. Hieda O, Kawasaki S, Wakimasu K, Yamasaki K, Inatomi T, Kinoshita S. Clinical outcomes of phototherapeutic keratectomy in eyes with Thiel-Behnke corneal dystrophy. Am J Ophthalmol. 2013;155(1):66-72.e1. PMID: 22967865. doi:10.1016/j.ajo.2012.06.022. PubMed

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